This competitive renewal application is focused on the characterization of cyclazocine, ethylketo-cyclazocine, and their enantiomers as novel anti-cocaine and anti-heroin medications. In recent years, this grant was directed at characterizing irreversible opioid compounds, synthesized by the late Dr. Sydney Archer. Drs. Mark P. Wentland and Arthur G. Schultz, both at Rensselaer Polytechnic Institute, are continuing Dr. Archer's work on the synthesis of compounds to treat drug abuse. While employed by Sterling-Winthrop, Dr. Wentland had extensive experience in the synthesis of analogs of cyclazocine. During the past two years, he has synthesized a number of analogues of cyclazocine and their enantiomers. Cyclazocine is a kappa opioid agonist and a mu opioid antagonist. Kappa agonists and mu antagonists decrease dopamine release in the nucleus accumbens, a primary pathway involved in the reinforcing effects of drugs of abuse. Therefore, kappa agonists and compounds with the properties of being kappa agonists and mu antagonists have the potential to be useful in treating drug abuse. Currently, cyclazocine is in a clinical trial as a possible medication for cocaine abuse. Recently, ethylketo-cyclazocine was shown to block cocaine self- administration in non-human primates. Therefore, derivatives of cyclazocine that do not have major side effects are potential medications for treating cocaine and heroin abuse. The proposed studies will characterize a number of cyclazocine, ketocyclazocine and ethylketocyclazocine derivatives for their affinity and selectivity for the mu, delta and kappa opioid receptors, using radioligand binding assays. Selective agonists and antagonists will be used to determine the selectivity and affinity for each compound in mouse antinociceptive tests. D50 values for agonists and pA2 values for antagonists will be determined. The goal of this proposal is to identify cyclazocine derivatives with kappa agonist activity and varying degrees of mu antagonist activity. Oral and systemic potency of selected compounds. Also, microdialysis will be used to determine if selected compounds will be inhibit cocaine-induced increases in dopamine levels in nucleus accumbens in rats. The characterization of novel cyclazocine derivatives will identify potential medications for treating cocaine and heroin abuse and will suggest the basic mechanisms responsible for the drug's action.